A homozygous IER3IP1 mutation causes microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (MEDS)

Abstract

Wolcott-Rallison syndrome (WRS) and the recently delineated microcephaly with simplified gyration, epilepsy, and permanent neonatal diabetes syndrome (MEDS) are clinically overlapping autosomal recessive disorders characterized by early onset diabetes, skeletal defects, and growth retardation. While liver and renal symptoms are more severe in WRS, neurodevelopmental characteristics are more pronounced in MEDS patients, in which microcephaly and uncontrolled epilepsy are uniformly present. Mutations in the EIF2AK3 gene were described in patients with WRS and defects in this gene lead to increased susceptibility to apoptotic cell death. Mutations in IER3IP1 have been reported in patients with MEDS and similarly, loss of activity results in apoptosis of neurons and pancreatic beta cells in patients. Here we report on a homozygous mutation of the IER3IP1 gene in four patients from two unrelated consanguineous Egyptian families presenting with MEDS who display burst suppression patterns on EEG. All patients presented with mildly elevated liver enzymes, microalbuminuria, and skeletal changes such as scoliosis and osteopenia, leading to repeated bone fractures. We expand the phenotypic spectrum of MEDS caused by IER3IP1 gene mutations and propose that WRS and MEDS are overlapping clinical syndromes, displaying significant gene-dependent clinical variability.

FIG. 1

The pedigree of the families included in the study.

FIG. 2

The facial features of Patients. Note narrow/short forehead with bitemporal grooving, anteverted nares, deep philtrum, and tented vermilion of upper lip.

FIG. 3

Radiograph of Patient 1. A: Osteopenia in carpal, metacarpal and phalanges with cone shaped proximal phalanges. B: Thin cortex of tibia and fibula with metaphyseal widening and osteopenia. C: Thin cortex of femora with severe osteopenia. D: Kyphosis, severe osteopenia with platyspondyly and osteopenic ribs.

FIG. 4

Cranial MRI of patients. First column: Rostral axial T1 weighted images show simplified gyral pattern, severe microcephaly, and different degree of ventriculomegaly, suggestive for cerebral atrophy. Second column: Caudal axial T1 weighted images showing brain atrophy and simplified gyral pattern. Third column: Sagittal images showing severely reduced volume of corpus callosum and cerebellar vermis hypoplasia.

FIG. 5

Sequence chromatograms of exon 3 of the IER3IP1 gene showing the point mutation c.T233C detected as homozygous in the affected patients from each family, heterozygous in both parents, and homozygous wildtype in both unaffected siblings.